One of the life-threatening and most severe complications of sickle cell disease is cerebral vascular disease. Some patients may experience small ischemic events that range from asymptomatic to mildly symptomatic. Other patients may experience complete occlusion of a large cerebral artery at a young age. These patient may quickly develop moya moya and deficient cerebral perfusion. Without chronic transfusion therapy or a bone marrow transplant, patients with significant cerebral vascular disease have a high risk for diseaserelated mortality by the third decade of life. Identification of risk factors for stroke will permit early preventative interventions prior to cerebral artery occlusion. . In the past few years, there have been several seminal publications of whole genome and whole exome sequencing applied patient-parent triads to define the genetic basis of disease in newborns. We will apply a similar approach to define potential genetic modifiers that predict risk and offer a better understanding of early onset large cerebral artery disease in children with sickle cell disease. We have identified and collected DNA samples on eight families with more than one child affected by sickle cell disease, but only one child with large cerebral artery occlusion. Instead of patient-parent triads, we will use the sibling as an additional control. Theoretically, it is possible for a parent without sickle cell disease to carry a mutation or single nucleotide polymorphism that predicts sickle cell associated cerebral vascular disease. However, in the absence of the sickle cell phenotype, there is no stroke phenotype. Another aim for this pilot is to develop the bioinformatic and computational biology expertise to pursure additional projects involving the application of next generation sequencing. To make this technology available for additional projects, we will develop and validate a quality assurance driven bioinformatics pipeline. This will be the focus of the second half of this pilot project. We will use the data obtained in patients with sickle cell disease to develop and validate the pipeline. This pipeline and approach will be scalable for larger future studies.